Sensitivity Analysis and Uncertainty Quantification of Nanoparticle Deposition from Tongue Morphological Variations.

The human tongue has highly variable morphology. Its role in regulating respiratory flows and deposition of inhaled aerosols remains unclear. The objective of this study was to quantify the uncertainty of nanoparticle deposition from the variability in tongue shapes and positions and to rank the importance of these morphological factors. Oropharyngeal models with different tongue postures were reconstructed by modifying an existent anatomically accurate upper airway geometry. An LRN k-ω model was applied to solve the multiregime flows, and the Lagrangian tracking approach with near-wall treatment was used to simulate the behavior and fate of inhaled aerosols. Once the database of deposition rates was completed, a surrogate model was trained using Gaussian process regression with polynomial kernels and was validated by comparing its predictions to new CFD simulations. Input sensitivity analysis and output updateability quantification were then performed using the surrogate model. Results show that particle size is the most significant parameter in determining nanoparticle deposition in the upper airway. Among the morphological factors, the shape variations in the central tongue had a higher impact on the total deposition than those in the back tongue and glottal aperture. When considering subregional deposition, mixed sensitivity levels were observed among morphological factors, with the back tongue being the major factor for throat deposition and the central tongue for oral deposition. Interaction effects between flow rate and morphological factors were much higher than the effects from individual parameters and were most significant in the throat (pharyngolaryngeal region). Given input normal variances, the nanoparticle deposition exhibits logarithmical normal distributions, with much lower uncertainty in 100-nm than 2-nm aerosols.

Assessing Nasal Epithelial Dynamics: Impact of the Natural Nasal Cycle on Intranasal Spray Deposition.

This study investigated the intricate dynamics of intranasal spray deposition within nasal models, considering variations in head orientation and stages of the nasal cycle. Employing controlled delivery conditions, we compared the deposition patterns of saline nasal sprays in models representing congestion (N1), normal (N0), and decongestion (P1, P2) during one nasal cycle. The results highlighted the impact of the nasal cycle on spray distribution, with congestion leading to confined deposition and decongestion allowing for broader dispersion of spray droplets and increased sedimentation towards the posterior turbinate. In particular, the progressive nasal dilation from N1 to P2 decreased the spray deposition in the middle turbinate. The head angle, in conjunction with the nasal cycle, significantly influenced the nasal spray deposition distribution, affecting targeted drug delivery within the nasal cavity. Despite controlled parameters, a notable variance in deposition was observed, emphasizing the complex interplay of gravity, flow shear, nasal cycle, and nasal morphology. The magnitude of variance increased as the head tilt angle increased backward from upright to 22.5° to 45° due to increasing gravity and liquid film destabilization, especially under decongestion conditions (P1, P2). This study's findings underscore the importance of considering both natural physiological variations and head orientation in optimizing intranasal drug delivery.

Optimized gravity-driven intranasal drop administration delivers significant doses to the ostiomeatal complex and maxillary sinus.

Chronic and allergic rhinosinusitis impacts approximately 12% of the global population. Challenges in rhinosinusitis treatment include paranasal sinus inaccessibility and variability in delivery efficiency among individuals. This study addresses these challenges of drug delivery by developing a high-efficiency, low-variability protocol for nasal drop delivery to the ostiomeatal complex (OMC) and maxillary sinus. Patient-specific nasal casts were dissected to reveal the configurations of conchae and meatus, providing insights into anatomical features amendable for sinus delivery. Fluorescent dye-enhanced videos visualized the dynamic liquid translocation in transparent nasal casts, allowing real-time assessment and quick adjustment to delivery parameters. Dosimetry to the OMC and maxillary sinus were quantified as drop count and mass using a precision scale. Key delivery factors, including the device type, formulation, and head-chin orientation, were systematically investigated in a cohort of ten nasal casts. Results show that both the squeeze bottle and soft-mist nasal pump yielded notably low doses to the OMC with high variability, and no dose from these two devices was detected within the maxillary sinuses. In contrast, the proposed approach, which included a curved nozzle surpassing the nasal valve and leveraged gravity-driven liquid translocation along the lateral nasal wall, delivered significant doses to the OMC and maxillary sinus. Iterative experimentations identified the optimal head tilt to be 40° and chin tilt to be° from the lateral recumbent position. Statistical analyses established the drop count required for effective OMC/sinus delivery. The proposed delivery protocol holds the potential to enhance chronic rhinosinusitis treatment outcomes with low variability. The dual role of nasal anatomy in posing challenges and offering opportunities highlights the need for future investigations using diverse formulations in a larger cohort of nasal models. Optimized gravity-driven intranasal drop administration delivers significant doses to the ostiomeatal complex and maxillary sinus.

Delivery of Agarose-aided Sprays to the Posterior Nose for Mucosa Immunization and Short-term Protection against Infectious Respiratory Diseases.

AIM: The study aimed to deliver sprays to the posterior nose for mucosa immunization or short-term protection. BACKGROUND: Respiratory infectious diseases often enter the human body through the nose. Sars-Cov-2 virus preferentially binds to the ACE2-rich tissue cells in the nasopharynx (NP). Delivering medications to the nose, especially to the NP region, provides either a short-term protective/therapeutic layer or long-term mucosa immunization. Hydrogel-aided medications can assist film formation, prolong film life, and control drug release. However, conventional nasal sprays have failed to dispense mediations to the posterior nose, with most sprays lost in the nasal valve and front turbinate. OBJECTIVE: The objective of the study was to develop a practical delivery system targeting the posterior nose and quantify the dosimetry distribution of agarose-saline solutions in the nasal cavity. METHOD: The solution viscosities with various hydrogel concentrations (0.1-1%) were measured at different temperatures. Dripping tests on a vertical plate were conducted to understand the hydrogel concentration effects on the liquid film stability and mobility. Transparent nasal airway models were used to visualize the nasal spray deposition and liquid film translocation. RESULT: Spray dosimetry with different hydrogel concentrations and inhalation flow rates was quantified on a total and regional basis. The solution viscosity increased with decreasing temperature, particularly in the range of 60-40 oC. The liquid viscosity, nasal spray atomization, and liquid film mobility were highly sensitive to the hydrogel concentration. Liquid film translocations significantly enhanced delivered doses to the caudal turbinate and nasopharynx when the sprays were administered at 60 oC under an inhalation flow rate of 11 L/min with hydrogel concentrations no more than 0.5%. On the other hand, sprays with 1% hydrogel or administered at 40 oC would significantly compromise the delivered doses to the posterior nose. CONCLUSION: Delivering sufficient doses of hydrogel sprays to the posterior nose is feasible by leveraging the post-administration liquid film translocation.

Nasal anatomy and sniffing in respiration and olfaction of wild and domestic animals.

Animals have been widely utilized as surrogate models for humans in exposure testing, infectious disease experiments, and immunology studies. However, respiratory diseases affect both humans and animals. These disorders can spontaneously affect wild and domestic animals, impacting their quality and quantity of life. The origin of such responses can primarily be traced back to the pathogens deposited in the respiratory tract. There is a lack of understanding of the transport and deposition of respirable particulate matter (bio-aerosols or viruses) in either wild or domestic animals. Moreover, local dosimetry is more relevant than the total or regionally averaged doses in assessing exposure risks or therapeutic outcomes. An accurate prediction of the total and local dosimetry is the crucial first step to quantifying the dose-response relationship, which in turn necessitates detailed knowledge of animals' respiratory tract and flow/aerosol dynamics within it. In this review, we examined the nasal anatomy and physiology (i.e., structure-function relationship) of different animals, including the dog, rat, rabbit, deer, rhombus monkey, cat, and other domestic and wild animals. Special attention was paid to the similarities and differences in the vestibular, respiratory, and olfactory regions among different species. The ventilation airflow and behaviors of inhaled aerosols were described as pertinent to the animals' mechanisms for ventilation modulation and olfaction enhancement. In particular, sniffing, a breathing maneuver that animals often practice enhancing olfaction, was examined in detail in different animals. Animal models used in COVID-19 research were discussed. The advances and challenges of using numerical modeling in place of animal studies were discussed. The application of this technique in animals is relevant for bidirectional improvements in animal and human health.

Visualization and Estimation of Nasal Spray Delivery to Olfactory Mucosa in an Image-Based Transparent Nasal Model.

Background: Nose-to-brain (N2B) drug delivery offers unique advantages over intravenous methods; however, the delivery efficiency to the olfactory region using conventional nasal devices and protocols is low. This study proposes a new strategy to effectively deliver high doses to the olfactory region while minimizing dose variability and drug losses in other regions of the nasal cavity. Materials and Methods: The effects of delivery variables on the dosimetry of nasal sprays were systematically evaluated in a 3D-printed anatomical model that was generated from a magnetic resonance image of the nasal airway. The nasal model comprised four parts for regional dose quantification. A transparent nasal cast and fluorescent imaging were used for visualization, enabling detailed examination of the transient liquid film translocation, real-time feedback on input effect, and prompt adjustment to delivery variables, which included the head position, nozzle angle, applied dose, inhalation flow, and solution viscosity. Results: The results showed that the conventional vertex-to-floor head position was not optimal for olfactory delivery. Instead, a head position tilting 45-60° backward from the supine position gave a higher olfactory deposition and lower variability. A two-dose application (250 mg) was necessary to mobilize the liquid film that often accumulated in the front nose following the first dose administration. The presence of an inhalation flow reduced the olfactory deposition and redistributed the sprays to the middle meatus. The recommended olfactory delivery variables include a head position ranging 45-60°, a nozzle angle ranging 5-10°, two doses, and no inhalation flow. With these variables, an olfactory deposition fraction of 22.7 ± 3.7% was achieved in this study, with insignificant discrepancies in olfactory delivery between the right and left nasal passages. Conclusions: It is feasible to deliver clinically significant doses of nasal sprays to the olfactory region by leveraging an optimized combination of delivery variables.

A Supine Position and Dual-Dose Applications Enhance Spray Dosing to the Posterior Nose: Paving the Way for Mucosal Immunization.

Delivering vaccines to the posterior nose has been proposed to induce mucosal immunization. However, conventional nasal devices often fail to deliver sufficient doses to the posterior nose. This study aimed to develop a new delivery protocol that can effectively deliver sprays to the caudal turbinate and nasopharynx. High-speed imaging was used to characterize the nasal spray plumes. Three-dimensional-printed transparent nasal casts were used to visualize the spray deposition within the nasal airway, as well as the subsequent liquid film formation and translocation. Influencing variables considered included the device type, delivery mode, release angle, flow rate, head position, and dose number. Apparent liquid film translocation was observed in the nasal cavity. To deliver sprays to the posterior nose, the optimal release angle was found to be 40° for unidirectional delivery and 30° for bidirectional delivery. The flow shear was the key factor that mobilized the liquid film. Both the flow shear and the head position were important in determining the translocation distance. A supine position and dual-dose application significantly improved delivery to the nasopharynx, i.e., 31% vs. 0% with an upright position and one-dose application. It is feasible to effectively deliver medications to the posterior nose by leveraging liquid film translocation for mucosal immunization.

Two-way coupling and Kolmogorov scales on inhaler spray plume evolutions from Ventolin, ProAir, and Qvar.

Previous numerical studies of pulmonary drug delivery using metered-dose inhalers (MDIs) often neglected the momentum transfer from droplets to fluid. However, Kolmogorov length scales in MDI flows can be comparable to the droplet sizes in the orifice vicinity, and their interactions can modify the spray behaviors. This study aimed to evaluate the two-way coupling effects on spray plume evolutions compared to one-way coupling. The influences from the mass loading, droplet size, and inhaler type were also examined. Large-eddy simulation and Lagrangian approach were used to simulate the flow and droplet motions. Two-way coupled predictions appeared to provide significantly improved predictions of the aerosol behaviors close to the Ventolin orifice than one-way coupling. Increasing the applied MDI dose mass altered both the fluid and aerosol dynamics, notably bending the spray plume downward when applying a dose ten times larger. The droplet size played a key role in spray dynamics, with the plume being suppressed for 2-µm aerosols and enhanced for 20-µm aerosols. The Kolmogorov length scale ratio dp/η correlated well with the observed difference in spray plumes, with suppressed plumes when dp/η < 0.1 and enhanced plumes when dp/η > 0.1. For the three inhalers considered (Ventolin, ProAir, and Qvar), significant differences were predicted using two-way and one-way coupling despite the level and manifestation of these differences varied. Two-way coupling effects were significant for MDI sprays and should be considered in future numerical studies.

Investigation of Mask Efficiency for Loose-Fitting Masks against Ultrafine Particles and Effect on Airway Deposition Efficiency.

Ultrafine particle (i.e., smaller than 100 nm) in the ambient air is a significant public health issue. The inhalation and deposition of ultrafine particles in the human airways can lead to various adverse health effects. Loose-fitting types of masks are commonly used by the general public in some developing countries for protecting against ultrafine particles in the ambient environment. This research conducted a series of laboratory chamber experiments using two sets of particle sizers and two mannequin heads to study the mask efficiency of selected loose-fitting masks. Results acquired demonstrated that the cloth mask showed a low mask efficiency against ultrafine particles with the mask efficiency generally less than 0.4. The KN95 presented a better mask efficiency among all tested masks with the mask efficiency overall larger than 0.5. In addition, the effect of mask-wearing on the change of ultrafine particle airway deposition efficiency was also investigated in this study. The ultrafine particle deposition efficiency in the airway section studied was found to decrease due to mask-wearing, and the decreases of the deposition efficiencies were similar among all loose-fitting masks tested.

Olfactory Drug Aerosol Delivery with Acoustic Radiation.

Nose-to-brain (N2B) drug delivery is a new approach to neurological disorder therapy as medications can bypass the blood-brain barrier and directly enter the brain. However, the delivery efficiency to the olfactory region using the conventional delivery method is impractically low because of the region's secluded position in a convoluted nasal cavity. In this study, the acoustic radiation force was explored as an N2B delivery alternative in a wide frequency range of 10-100,000 Hz at an increment of 50 Hz. Numerical simulations of the particle deposition in the olfactory region of four nasal configurations were performed using COMSOL. Frequency analysis of the nasal cavities revealed that eigenfrequencies were often associated with a specific region with narrow passages and some eigenfrequencies exhibited an amendable pressure field to the olfactory region. Transient particle tracking was conducted with an acoustic inlet at 1 Pa, and a frequency spectrum of 10-100,000 Hz was imposed on the airflow, which carried the particles with acoustic radiation forces. It was observed that by increasing the pulsating wave frequency at the nostrils, the olfactory delivery efficiency reached a maximum in the range 11-15 kHz and decreased after that. The correlation of the olfactory delivery efficiency and instantaneous values of other parameters such as acoustic velocity and pressure in the frequency domain was examined.

Lower Inspiratory Breathing Depth Enhances Pulmonary Delivery Efficiency of ProAir Sprays.

Effective pulmonary drug delivery using a metered-dose inhaler (MDI) requires a match between the MDI sprays, the patient's breathing, and respiratory physiology. Different inhalers generate aerosols with distinct aerosol sizes and speeds, which require specific breathing coordination to achieve optimized delivery efficiency. Inability to perform the instructed breathing maneuver is one of the frequently reported issues during MDI applications; however, their effects on MDI dosimetry are unclear. The objective of this study is to systemically evaluate the effects of breathing depths on regional deposition in the respiratory tract using a ProAir-HFA inhaler. An integrated inhaler mouth-throat-lung geometry model was developed that extends to the ninth bifurcation (G9). Large-eddy simulation (LES) was used to compute the airflow dynamics due to concurrent inhalation and orifice flows. The discrete-phase Lagrangian model was used to track droplet motions. Experimental measurements of ProAir spray droplet sizes and speeds were used as initial and boundary conditions to develop the computational model for ProAir-pulmonary drug delivery. The time-varying spray plume from a ProAir-HFA inhaler into the open air was visualized using a high-speed imaging system and was further used to validate the computational model. The inhalation dosimetry of ProAir spray droplets in the respiratory tract was compared among five breathing depths on a regional, sub-regional, and local basis. The results show remarkable differences in airflow dynamics within the MDI mouthpiece and the droplet deposition distribution in the oral cavity. The inhalation depth had a positive relationship with the deposition in the mouth and a negative relationship with the deposition in the five lobes beyond G9 (small airways). The highest delivery efficiency to small airways was highest at 15 L/min and declined with an increasing inhalation depth. The drug loss inside the MDI was maximal at 45-60 L/min. Comparisons to previous experimental and numerical studies revealed a high dosimetry sensitivity to the inhaler type and patient breathing condition. Considering the appropriate inhalation waveform, spray actuation time, and spray properties (size and velocity) is essential to accurately predict inhalation dosimetry from MDIs. The results highlight the importance of personalized inhalation therapy to match the patient's breathing patterns for optimal delivery efficiencies. Further complimentary in vitro or in vivo experiments are needed to validate the enhanced pulmonary delivery at 15 L/min.

Count- and mass-based dosimetry of MDI spray droplets with polydisperse and monodisperse size distributions.

Most previous numerical studies of inhalation drug delivery used monodisperse aerosols or quantified deposition as the ratio of deposited particle number over the total number of released particles (i.e., count-based). These practices are reasonable when the aerosols have a sufficiently narrow size range. However, spray droplets from metered-dose inhalers (MDIs) are often polydisperse with a wide size range, so using monodisperse aerosols and/or count-based deposition quantification may lead to significant errors. The objective of this study was to develop a mass-based dosimetry method and evaluate its performance in lung delivery in a mouth-lung (G9) geometry with an albuterol-CFC inhaler. The conventional practices (monodisperse and polydisperse-count-based) were also simulated for comparison purposes. The MDI actuation in the open space was studied using both high-speed imaging and LES-Lagrangian simulations. Experimentally measured spray velocities and size distribution were implemented in the computational model as boundary conditions. Good agreement was achieved between recorded and simulated spray plume evolution spatially and temporally. The polydisperse-mass-based predictions of MDI doses compared favorably with the measurements in all three regions considered (device, mouth-throat, and lung). Significant errors in MDI regional deposition were predicted using the monodisperse and count-based methods. The new polydisperse-mass-based method also predicted local deposition hot spots that were one order of magnitude higher in intensity than the two conventional methods. The results of this study highlighted that a presentative polydisperse size distribution and appropriate deposition quantification method should be applied to reliably predict the MDI drug delivery in the human respiratory tract.

Effect of MDI Actuation Timing on Inhalation Dosimetry in a Human Respiratory Tract Model.

Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation-inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI-mouth-lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth-throat, and lung. Concerning the device-patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth-throat loss and increased lung doses in both the central and peripheral regions.

Liquid Film Translocation Significantly Enhances Nasal Spray Delivery to Olfactory Region: A Numerical Simulation Study.

Previous in vivo and ex vivo studies have tested nasal sprays with varying head positions to enhance the olfactory delivery; however, such studies often suffered from a lack of quantitative dosimetry in the target region, which relied on the observer's subjective perception of color changes in the endoscopy images. The objective of this study is to test the feasibility of gravitationally driven droplet translocation numerically to enhance the nasal spray dosages in the olfactory region and quantify the intranasal dose distribution in the regions of interest. A computational nasal spray testing platform was developed that included a nasal spray releasing model, an airflow-droplet transport model, and an Eulerian wall film formation/translocation model. The effects of both device-related and administration-related variables on the initial olfactory deposition were studied, including droplet size, velocity, plume angle, spray release position, and orientation. The liquid film formation and translocation after nasal spray applications were simulated for both a standard and a newly proposed delivery system. Results show that the initial droplet deposition in the olfactory region is highly sensitive to the spray plume angle. For the given nasal cavity with a vertex-to-floor head position, a plume angle of 10° with a device orientation of 45° to the nostril delivered the optimal dose to the olfactory region. Liquid wall film translocation enhanced the olfactory dosage by ninefold, compared to the initial olfactory dose, for both the baseline and optimized delivery systems. The optimized delivery system delivered 6.2% of applied sprays to the olfactory region and significantly reduced drug losses in the vestibule. Rheological properties of spray formulations can be explored to harness further the benefits of liquid film translocation in targeted intranasal deliveries.

Inhalation dosimetry of nasally inhaled respiratory aerosols in the human respiratory tract with locally remodeled conducting lungs.

Objective: Respiratory diseases are often accompanied by alterations to airway morphology. However, inhalation dosimetry data in remodeled airways are scarce due to the challenges in reconstructing diseased respiratory morphologies. This study aims to study the airway remodeling effects on the inhalation dosimetry of nasally inhaled nanoparticles in a nose-lung geometry that extends to G9 (ninth generation).Materials and methods: Statistical shape modeling was used to develop four diseased lung models with varying levels of bronchiolar dilation/constriction in the left-lower (LL) lobe (i.e. M1-M4). Respiratory airflow and particle deposition were simulated using a low Reynolds number k-ω turbulence model and a Lagrangian tracking approach.Results: Significant discrepancies were observed in the flow partitions between the left and right lungs, as well as between the lower and upper lobes of the left lung, which changed by 10-fold between the most dilated and constricted models.Much lower doses were predicted on the surface of the constricted LL bronchioles G4-G9, as well as into the peripheral airways beyond G9 of the LL lung. However, the LL lobar remodeling had little effect on the dosimetry in the nasopharynx, as well as on the total dosimetry in the nose-lung geometry (up to G9).Conclusion: It is suggested that airway remodeling may pose a higher viral infection risk to the host by redistributing the inhaled viruses to healthy lung lobes. Airway remodeling effects should also be considered in the treatment planning of inhalation therapies, not only because of the dosimetry variation from altered lung morphology but also its evolution as the disease progresses.

A comparison of CFPD, compartment, and uniform distribution models for radiation dosimetry of radionuclides in the lung.

Radioactive aerosols that arise from natural sources and nuclear accidents can be a long-term hazard to human health. Despite the heterogeneous particle deposition in the respiratory tract, uniform aerosol doses have long been assumed in respiratory radiation dosimetry predictions, such as in the compartment and uniform distribution models. It is unclear how these deposition patterns affect internal radiation doses, which are critical in the health assessment of radioactive hazards. This work seeks to quantify the radio-dosimetry sensitivity to initial deposition patterns by comparing computational and compartment/uniform models. A new approach was developed to implement the compartment model into voxel phantoms (e.g. VIP-man) for radiation dosimetry. The calculated radiation fluence, energy deposition density and organ doses were compared to those obtained from coupling computational fluid-particle dynamics (CFPD) with Monte Carlo radiation transport and to those obtained from uniform source distribution approximation. The results show that the source particle distribution within the respiratory system substantially influences the radiation dosimetry distribution. The compartment and uniform models underestimated aerosol deposition in the crania ridge, leading to lower doses in the trachea and surrounding organs. For 0.5 MeV gammas, the CFPD-Monte Carlo N-particle (MCNP) model predicted a tracheal dose twice that of the compartment model and four times the uniform model. For 1 MeV betas, the CFPD-MCNP-predicted tracheal dose is 2.6 times that of the compartment model and 14 times the uniform model. Compared to the compartment/uniform models, the CFPD approach predicted a 50% lower beta dose in the lung but higher beta doses in the heart (six times), liver (four times) and stomach (2.5 times). It is suggested that including compartments for the lung periphery and tracheal carina ridge may improve the dosimetry accuracy of compartment models.

Leveraging statistical shape modeling in computational respiratory dynamics: Nanomedicine delivery in remodeled airways.

BACKGROUND AND OBJECTIVE: Accurate knowledge of the delivered doses to the diseased site in the respiratory tract is crucial to elicit desired therapeutic outcomes. However, such information is still difficult to obtain due to inaccessibility for measurement or visualization, complex network structure, and challenges in reconstructing lung geometries with disease-invoked airway remodeling. This study presents a novel method to simulate the airway remodeling in a mouth-lung geometry extending to G9. METHODS: Statistical shape modeling was used to extract morphological features from a lung geometry database and four new models (i.e., M1-M4) were generated with parameter-controlled dilated/constricted bronchioles in the left-lower (LL) lung. The variations in airflow and particle deposition due to the airway remodeling were simulated using a well-tested k-ω turbulence model and a Lagrangian tracking approach. RESULTS: Significant variations in flow partitions between the lower and upper lobes of the left lung, as well as between the left and right lungs. The flow partition into the LL lobe varied by 10-fold between the most dilated and constricted models in this study. Significantly lower doses were also predicted on the surface of the constricted LL bronchioles G4-G9, as well as into the peripheral airways beyond G9. However, the total dosimetry in the mouth-lung geometry (up to G9) exhibited low sensitivity to the LL lobar remodeling. Results in this study suggest that the optimal nanomedicine should be 2-10 nm in diameter if targeted at the constricted bronchioles G4-G9 as in topical inhalation therapy but should be larger than 20 nm if targeted at the alveolar region as in systemic therapy. CONCLUSIONS: This study highlights the large dose variability from local airway remodeling and the need to consider these variations in the treatment planning for pneumonia and other obstructive respiratory diseases.

SARS COV-2 virus-laden droplets coughed from deep lungs: Numerical quantification in a single-path whole respiratory tract geometry.

When an infected person coughs, many virus-laden droplets will be exhaled out of the mouth. Droplets from deep lungs are especially infectious because the alveoli are the major sites of coronavirus replication. However, their exhalation fraction, size distribution, and exiting speeds are unclear. This study investigated the behavior and fate of respiratory droplets (0.1-4 µm) during coughs in a single-path respiratory tract model extending from terminal alveoli to mouth opening. An experimentally measured cough waveform was used to control the alveolar wall motions and the flow boundary conditions at lung branches from G2 to G18. The mouth opening was modeled after the image of a coughing subject captured using a high-speed camera. A well-tested k-ω turbulence model and Lagrangian particle tracking algorithm were applied to simulate cough flow evolutions and droplet dynamics under four cough depths, i.e., tidal volume ratio (TVR) = 0.13, 0.20. 0.32, and 0.42. The results show that 2-µm droplets have the highest exhalation fraction, regardless of cough depths. A nonlinear relationship exists between the droplet exhalation fraction and cough depth due to a complex deposition mechanism confounded by multiscale airway passages, multiregime flows, and drastic transient flow effects. The highest exhalation fraction is 1.6% at the normal cough depth (TVR = 0.32), with a mean exiting speed of 20 m/s. The finding that most exhaled droplets from deep lungs are 2 µm highlights the need for more effective facemasks in blocking 2-µm droplets and smaller both in infectious source control and self-protection from airborne virus-laden droplets.